Spinal cord injury (SCI) is a devastating condition that can arise from
mechanical trauma to the spinal cord, or from a variety of non-traumatic
insults, such as infection, oncogenesis, birth trauma, and electrocution
[1]. Regardless of the cause, SCI will result in either complete or partial
loss of motor and sensory function below the lesion site [2], as well
as some degree of autonomic dysfunction [3]. SCI will often result in
severe loss of tissue and varying degrees of functional impairment, and,
after SCI, the spinal cord exhibits only limited repair [4]. This can have
debilitating effects on the quality of life, and even the life expectancy, of
SCI patients [5].

Spinal cord injury (SCI) is a devastating condition that can arise from
mechanical trauma to the spinal cord, or from a variety of non-traumatic
insults, such as infection, oncogenesis, birth trauma, and electrocution
[1]. Regardless of the cause, SCI will result in either complete or partial
loss of motor and sensory function below the lesion site [2], as well
as some degree of autonomic dysfunction [3]. SCI will often result in
severe loss of tissue and varying degrees of functional impairment, and,
after SCI, the spinal cord exhibits only limited repair [4]. This can have
debilitating effects on the quality of life, and even the life expectancy, of
SCI patients [5].

In the adult population, the majority of SCI results from motor vehicle
accidents (MVA) [6]. In infants and children, the common causes of SCI
include trauma, resulting from MVA and sports injury, but also from
infections, neoplasms, congenital malformations, and birth trauma [7].
The majority of SCI occur at the cervical level [2], resulting in more severe
autonomic dysfunction and a greater loss of function in the body than a
similar injury lower in the cord. SCI has a high cost to the community,
both financially and socially, although there is a lack of accurate
epidemiological data available in many countries [1]. A 2007 estimate of
the global incidence of spinal cord injury resulting from trauma (TSCI)
was 23 cases per million population each year [1]. Less is known about
pediatric SCI, as it is rarer, accounting for only 1-13% of all SCI [7-10];
however, pinning down an exact figure is difficult as different studies
use different age ranges and different parameters to assess the injury
based on hospital admissions, ASIA score and associated co-morbidities
[7-10]. In the pediatric SCI population, the majority of injuries result
from non-traumatic SCI, with traumatic spinal cord injury (TSCI) being
much less common [7].

SCI has a biphasal pathophysiology consisting of the primary,
immediate injury and a prolonged, exacerbating secondary injury phase
[18-21]. There is little that can be done in the primary injury phase and
the secondary damage phase of SCI is complex and changes over time,
making it difficult to identify a simple therapeutic target to alleviate its
detrimental effects. This injury phase involves multiple mechanisms and
systems, not the least of which is the inflammatory response, however we
still have little understanding of how these may differ between mature
and pediatric patients and animal models. The inflammatory response
plays a significant role in the profile of the microenvironment of the
lesion after SCI, as do the actions of reactive astrocytes and activated
endogenous microglia [22]. This basic pathophysiology is common to SCI
in both adult and developing cords. The majority of SCI research has been
carried out in animal models with a variety of different mammals used
in adult models, including non-human primates. Pediatric models have
used pigs [23], cats [24-26], and possums [27] as well as the common use of mice [28-30] and rats. This has given a broad view of the
similar response in a wide range of mammals, although little
has been corroborated in humans. However, as mammals,
it is thought that humans will exhibit a similar response
to that of the experimental animals used in research [31].
The developing spinal cord exhibits significant difference to
the fully developed adult cord in a variety of aspects, from
biomechanical [32-34], cellular and structural [23,35,36] to
molecular [28,37-39]. There is also a trend for infants having
a better recovery from analogous injury than their adult
counterparts, that bears greater scrutiny [14,32,35,40,41].

All of this causes some difficulty in exploring SCI in the
pediatric population experimentally. Despite the prevalence
of non-traumatic SCI in the pediatric population the vast
majority of work exploring pediatric SCI is performed using
traumatic models of injury. This is due to the complexities in
creating an infant model; traumatic models are logistically
easier, more readily reproducible and comparable to similar
models in adults. We also have only a limited understanding
of the analogous ages between the model animals and
human development, as well as the developmental timing.
The developmental timing, and especially the landmark
development stages, are poorly understood in our model
animals which creates difficulty in aligning these models
with the same landmarks in human development. This
alignment is necessary to account for the impact that the
development of the spinal cord, CNS and exogenous systems
is having on the response to a SCI in the pediatric population.
To further validate these models, allow for greater utility in
studying the pathophysiology of SCI and for the development
of potential therapies a deeper understanding of the model
animals themselves is essential.

The ‘normal’ behavior of infant and neonatal animals
is inherently different to that in fully developed adults,
and changes with different stages of development, which
also adds another layer of complexity to analyzing models
of pediatric SCI. In a pediatric model of SCI, it is hard to
accurately ascertain where development ends and recovery
begins. Very little is known about how much of an impact
the developmental state and plasticity of young spinal cords
has on injury recovery and the potential of ‘rewiring’ around
the injury. This is further complicated by the presence of
central pattern generation in the spinal cord. Central pattern
generation allows for the development of reflex movements,
without significant input from descending pathways and is
common in infant animals. This complicates the assessment
of locomotor function in these animals after injury.

SCI in the pediatric population may be rarer, however
it is an injury that incurs literally ‘life-long’ ramifications.
Unfortunately, we still understand very little about how
the developing spinal cord responds to injury, or how the
state of development affects this response. Pediatric SCI
is quite a unique injury and therefore presents unique
challenges on a clinical level, as well as ongoing challenges
for the patient due to its great effect on ongoing physical and
psycho-social development [42]. Injury presentation and
aetiology of pediatric SCI is different to that in mature adults
on a basic and clinical level, and a greater understanding of the mechanisms behind SCI in younger subjects is needed
to assist in the clinical management of these patients.
The development of clinically relevant animal models is
challenging and still requires substantial exploration. While
current traumatic SCI models have found some promising
avenues of research and a trend of better recovery in younger
animals the developmental and behavioral complexities
inherent in a pediatric model of SCI need to be addressed.
And finally, a greater effort needs to be devoted to finding
models to understand the progression of non-traumatic
injuries as well as the post-injury sensory and autonomic
impacts.